title: Calcium ions and osteoclastogenesis initiate the induction of bone formation by coral-derived macroporous constructs.
abstract: Coral-derived calcium carbonate/hydroxyapatite macroporous constructs of the genus Goniopora with limited hydrothermal conversion to hydroxyapatite (7% HA/CC) initiate the induction of bone formation. Which are the molecular signals that initiate pattern formation and the induction of bone formation? To evaluate the role of released calcium ions and osteoclastogenesis, 7% HA/CC was pre-loaded with either 500 μg of the calcium channel blocker, verapamil hydrochloride, or 240 μg of the osteoclast inhibitor, biphosphonate zoledronate, and implanted in the rectus abdominis muscle of six adult Chacma baboons Papio ursinus. Generated tissues on days 15, 60 and 90 were analysed by histomorphometry and qRT-PCR. On day 15, up-regulation of type IV collagen characterized all the implanted constructs correlating with vascular invasion. Zoledronate-treated specimens showed an important delay in tissue patterning and morphogenesis with limited bone formation. Osteoclastic inhibition yielded minimal, if any, bone formation by induction. 7% HA/CC pre-loaded with the Ca(++) channel blocker verapamil hydrochloride strongly inhibited the induction of bone formation. Down-regulation of bone morphogenetic protein-2 (BMP-2) together with up-regulation of Noggin genes correlated with limited bone formation in 7% HA/CC pre-loaded with either verapamil or zoledronate, indicating that the induction of bone formation by coral-derived macroporous constructs is via the BMPs pathway. The spontaneous induction of bone formation is initiated by a local peak of Ca(++) activating stem cell differentiation and the induction of bone formation.
authors.affiliation: Bone Research Laboratory, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Roland M
authors.initials: RM
authors.lastname: Klar
authors.forename: Raquel
authors.initials: R
authors.lastname: Duarte
authors.forename: Therese
authors.initials: T
authors.lastname: Dix-Peek
authors.forename: Caroline
authors.initials: C
authors.lastname: Dickens
authors.forename: Carlo
authors.initials: C
authors.lastname: Ferretti
authors.forename: Ugo
authors.initials: U
authors.lastname: Ripamonti
mesh_terms: D000818:Animals; D037421:Anthozoa / Q000737:chemistry*; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D001861:Bone Regeneration; D018786:Bone Substitutes / Q000737:chemistry*; D002118:Calcium / Q000502:physiology*; D002119:Calcium Carbonate / Q000737:chemistry*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology; D017886:Durapatite / Q000737:chemistry; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology*; D048549:Papio ursinus; D016062:Porosity; D019736:Prostheses and Implants; D014700:Verapamil / Q000494:pharmacology; D000099176:Noggin Protein
chemical_list: D050071:Bone Density Conservation Agents; D055396:Bone Morphogenetic Protein 2; D018786:Bone Substitutes; D002118:Calcium; D002119:Calcium Carbonate; D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D024141:Collagen Type IV; D004164:Diphosphonates; D017886:Durapatite; D014700:Verapamil; D000099176:Noggin Protein
keywords: Ca++; calcium channel blocker verapamil hydrochloride; functionalized nano-patterned topographies; osteoclast inhibitor biphosphonate zoledronate; qRT-PCR